General (including evidence of efficacy)

Nitroglycerin, intravenously administered

Intravenously administered nitroglycerin has several applications in clinical medicine (e.g., unstable angina, symptomatic heart failure), but we will focus on its use in heart failure.

Differences between drugs within the class

IV nitroglycerin is considerably less powerful throughout its dose range than nitroprusside.

Administration

IV nitroglycerin is generally started at 0.20 mcg/kg/min (10 to 15 mcg/min) and titrated upward until the therapeutic endpoints are achieved. These endpoints include relief of symptoms (dyspnea), significant change in systemic blood pressure, a certain level of pulmonary capillary wedge pressure, or development of side effects. Doses rarely exceed 6.0 to 7.0 mcg/kg/min (400 to 500 mcg/min).

Onset of action is 3 to 10 minutes and it takes 10 to 20 minutes for the effects to dissipate after discontinuation of the infusion. Nonpolyvinyl tubing and glass containers are used to prevent loss of the drug through absorbency. Nitroglycerin is cleared by glutathione-nitrate reductase, hydrolysis, direct removal by vasculature, and other less well-defined mechanisms.

Because nitroglycerin is far less aggressive as a vasodilator with slower onset of action than nitroprusside, the placement of an indwelling arterial line and pulmonary artery catheter are rarely used or indicated during administration; a less stable clinical setting may still warrant their use.

Pharmacologic action

Nitroglycerin acts through the NO receptor to activate guanylyl cyclase to increase cGMP and perhaps through other yet undefined mechanisms.

IV nitroglycerin reduces left ventricular diastolic pressure, pulmonary capillary wedge pressure, right ventricular diastolic pressure and right atrial pressure. With continued advancement of dose, there is also a fall in systemic and pulmonary vascular resistance, with a consequent modest rise in cardiac output. Some of the improved hemodynamics is also related to a decrease in mitral regurgitation. Again, the hemodynamic effects are less dramatic than those noted for nitroprusside.

The hemodynamic responses to nitroglycerin tend to gradually decrease with time. Starting as early as 12 to 24 hours into the infusion, the central hemodynamic effects tend to gradually return toward baseline; increasing the dose (infusion rate) may be effective in reversing this trend, but not uniformly so.

This waning of the response has not been fully elucidated, but activation of counteracting neurohormones, increased sensitivity to vasoconstrictors, desensitization of guanylate cyclase, and internal fluid shifts (to increase intravascular volume) have been proposed.

Indications and contraindications

Indications

IV nitroglycerin can be used to offer relief to patients with moderate to marked dyspnea. A common application is in a patient with occlusive coronary artery disease, symptomatic with dyspnea and with or without angina.

Nitroglycerin's favorable effects on myocardial ischemia, myocardial perfusion, coronary blood flow and platelet aggregation support its use in this setting. IV nitroglycerin may also improve coronary blood flow, myocardial perfusion, and energetics simply by dropping ventricular diastolic pressure greater than the fall in aortic diastolic pressure, thus allowing an augmentation of myocardial diastolic perfusion pressure. It is not uncommon for IV nitroglycerin to lower heart rate by reducing dyspnea and related symptoms, such that there is also an increase in coronary perfusion time.

While IV nitroglycerin can offer relief for severe dyspnea, as might occur with a ruptured papillary muscle or acute aortic valvular insufficiency, it rarely offers satisfactory relief of symptoms; nitroprusside is generally a better choice for severe cardiogenic dyspnea.

Contraindications

Intolerance to nitrates (e.g., severe headache) may limit their use. Hypotension may occur if administered to patients with an inadequately low ventricular filling pressure. A rare patient may experience sinus bradycardia and sinus arrest.

Undesirable effects

Headache and flushing are the most common side effects; the former often limits dose advancement until the headache subsides. Nausea and vomiting can occur, but generally associated with a severe headache.

Systemic hypotension, generally from excessive or rapid advancement of dosing, can occur and should be avoided in patients with critical, high grade coronary disease. The hypotension responds within 10 to 15 minutes after dose reduction or discontinuation. Prolonged infusions can result in fluid retention and edema. Marked bradycardia is a rare complication.

The development of pharmacodynamic tolerance with a continuous infusion is a common undesirable effect and is discussed above.

Alternative approaches

For mild to moderate dyspnea of heart failure, there are a number of alternative approaches, including diuretics, oral or sublingual nitrates, and other heart failure therapies (e.g., nesiritide).

For severe dyspnea, nitroprusside, diuretics, and other supportive measures offer a better choice.

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